Thalass. Rep., Volume 1, Issue s2 (December 2011) – 33 articles

Thalassemia major (TM) is the most common deadly genetic disorder, a major cause of chronic non-infectious morbidity and financial burden in many low and middle-income regions. In these settings few children reach adulthood because proper long-term supportive care is seldom available. Bone marrow transplantation (BMT) is the only available curative modality and it can be very successful and cost-effective for young children with low-risk features and a compatible related donor. However, in countries where TM is most prevalent, there is a dire shortage of BMT centers. The Cure2Children Foundation has supported a feasibility study evaluating safety, efficacy and costs of developing a new BMT center in an underserved lower-middle-income country with relatively untrained professionals within a structured collaboration and knowledge-transfer program. A total of 24 consecutive patients who underwent BMT in Pakistan between September 2008 and August 2010 are included in this prospective analysis, 17 from an established bone marrow transplant center, the National Institute for Blood Diseases in Karachi, Pakistan and the initial 7 BMTs from a start up unit in a government civil hospital, the Pakistan Institute of Medical Sciences Children’s Hospital in Islamabad. Patients were matched for age, nutritional status, growth, disease, disease status and post-BMT follow-up time. All patients had a matched-related sibling donor, were younger than 10 years of age at the time of transplantation, received the same conditioning regimen. All needy families could rely on a support program throughout the 8-month post-transplant period. The Cure2Children Foundation provided professional and financial support as well as a structured web-based data management and cooperation platform. At a median follow up of 19.6 months (range 8.7 to 31.5) actuarial thalassemia-free survival is 85.6% and 85.7% and overall survival 94.1% and 85.7% in the established and start-up center respectively with no statistically significant differences. Other outcome indices like infectious complications, engraftment parameters, transplant-related complications, and post-BMT performance scores also did not differ. The median cost of matched-related transplants in the start-up center, including pre-BMT evaluation, was 11,513 USD (range 7518 to 21,176). Within structured cooperation strategies bone marrow transplantation for thalassemia major can be performed safely, effectively, and affordably even in start-up centers in lower-middleincome countries, like Pakistan, were most thalassemia patients live. This observation may have important implications to increase access to cure for thalassemia worldwide.

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Bone marrow transplantation (BMT) is the only possible curative treatment for β-thalassemia major. The largest experience occurred in Pesaro, Italy, where the BMT was applied after a standard risk assessment. The patients were divided into 3 risk classes based on liver size by physical examination, the presence or absence of fibrosis by liver biopsy, and adherence to regular iron chelation. Outcomes were mainly affected by the risk status. After modifications to the conditioning regimens, the risk of transplantation-related complications in highrisk recipients reduced considerably. As a result, outcomes after transplantation have become more similar across risk categories. For BMT, most centers use bone marrow instead of peripheral blood in thalassemia. Some studies showed that peripheral blood stem cell transplantation (PBSCT) is better than BMT with regard to hematologic recovery, hospitalization period, leukemia-free survival, overall survival (OS), and transplant-related mortality (TRM). No significant differences were seen in grade II to IV acute GVHD (aGVHD); but the incidence of chronic GVHD (cGVHD) was significantly higher in the PBSCT group. BMT from unrelated donors may offer similar results to those obtained using HLA-identical family donors, at least for patients who are not fully compliant with conventional treatment and do not yet show severe complications of iron overload. All studies conclude that MUD BMT might be a good alternative for patients with less risk factors. Another study concluded that, at present, due to high graft failure and GVHD rates, BMT from alternative donors should be restricted to patients who have poor life expectancies because they cannot receive adequate conventional treatment or because of alloimmunization to minor blood antigens. In another study unrelated cord blood transplantation (CBT) was compared to related donor transplantation for children with β-thalassemia. The results were comparable to the survival rates of related-donor BMT for thalassemia. It has always been a dream for parents to have a new baby who might be a donor for his/her sibling and save his/her life. Today some families tried to learn the HLA group of the fetus using prenatal diagnosis. The last step in this development was preimplantation genetic diagnosis (PGD). PGD has become available as an alternative to prenatal diagnosis in order to avoid the risk for pregnancy termination, because PGD allows selection of unaffected embryos before a pregnancy is established. Gene therapies, the ultimate idea, involves replacing allogeneic stem cell transplantation with the transfer of normal globin genes into patientderived autologous haematopoietic stem cells, bypassing the need for allogeneic donors and the immunosuppression required to achieve engraftment of the transplanted cells and to eliminate the risk of donor-related graft-versus-host disease. The successful preclinical studies in thalassaemia mousemodels, the accumulating data on lentiviral vector-mediated HSC transduction and the anticipated increased safety of lineage-restricted globin SIN lentiviral vectors strongly support the initiation of Phase I gene therapy clinical trials in β-thalassaemia. Full article

Fetal globin is endogenous, normally integrated in hematopoietic stem cells in all humans, and available for reactivation. Inducing expression of fetal globin (γ-globin) gene expression to 60–70% of α globin synthesis produces β-thalassemia trait globin synthetic ratios, and has been shown to reduce anemia to mild levels which do not require regular blood transfusion. Several classes of therapeutics have induced γ-globin expression in β thalassemia patients, raised total hemoglobin levels, and even eliminated transfusion requirements in formerly transfusion-dependent patients, demonstrating proof-of-concept of the approach. However, prior generations of therapeutics were not readily feasible for widespread use. Currently, several recently discovered oral therapeutic candidates are more potent and/ or patientfriendly, requiring low oral doses, have distinct molecular mechanisms of action, and can be used in combination regimens. Tailoring therapeutic regimens to patient subsets stratified for solely β⁺ or a β⁰ globin mutation, and for quantitative trait loci (QTL) which modulate HbF and clinical severity, can guide more effective and informative clinical trials. These advancements provide methods for a rational approach to applying fetal globin gene induction in therapeutic regimens suitable for use in diverse thalassemia patient populations world-wide.

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The clinical manifestations of β-thalassemia are extremely heterogeneous, ranging from severe transfusion-dependent anemia, to the mild non transfusion dependent thalassemia intermedia and to the asymptomatic carrier state. The remarkable phenotypic variability is primary due to variations in the different globin genes (primary gene modifiers). The main pathophysiological determinant of the severity of β-thalassemia syndromes is the extent of α/non-α globin chain imbalance. Therefore, any factor capable of reducing the globin chain imbalance may have an ameliorating effect on the clinical picture. The most common mechanisms responsible of the amelioration of the phenotype are mild or silent β thalassemia alleles, coinheritance of α thalassemia, or of genetic determinants associated with increased γ globin chain production. Rarely, other complex mechanisms including dominantly inherited β thalassemia, somatic deletion of β globin gene and coinheritance of extra α globin genes with heterozygous β thalassemia have been reported. In addition to the variability of the phenotype resulting from primary gene modifiers, other genetic factors (secondary gene modifiers), mapping outside the β and α globin cluster, may influence the disease complications. Among these factors the ones best so far defined are those affecting bilirubin, iron and bone metabolism. However, the new methods of DNA analysis (i.e., GWAS and related methods) are expect expand the number of genes or gene variants involved in the phenotypic variability and in the response to treatment of β thalassemia.
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Preimplantation Genetic Diagnosis (PGD) is currently an alternative for couples with high risk of pregnancies with genetic anomalies; it offers the possibility of avoiding the need to terminate affected pregnancies, since it allows the selection of unaffected embryos for transfer. PGD for inherited disorders has become extremely accurate (99.5%), and may currently be performed for any single gene disorders in which mutation is identified. PGD has been performed for more than 100 different conditions resulting in the birth of at least 1000 healthy children free of genetic disorder. PGD is presently also used together with preimplantation HLA typing for treatment of affected sibling with genetic and acquired disorders requiring HLA matched stem cell transplantation. This is not only to allow couples to have an unaffected child but also to select a potential donor progeny for stem cell transplantation. In Turkey, thalassemia is the most commonly seen genetic disorder the rate of thalassemia carriers is about 3–4% in Turkey. The majority of our PGD cases are thalassemia carriers. They do not only require thalassemia mutation analysis but also HLA typing for their affected child. In this study PGD results of 236 Turkish couples with or without HLA typing will be presented and discussed. A full diagnosis was achieved in 91.0% of the biopsied samples. In Group I, 17.8% of the analyzed embryos were found to be HLA compatible. HLA compatible and disease free embryos were 12.9% of all diagnosed embryos. In group II, 17.2% of embryos were found to be HLA matched and 71.4% HLA non-matched. The majority of our HLA typing combined with PGD cases were β-Thalassemia carriers (87.9%). The mutations analyzed have high heterogeneity, the most frequent mutation was IVS-I-110 G-A and comprised 46.2% of all mutations. To date, 70 healthy and HLA compatible children have been born. Twenty-five sick children have already been cured with cord blood cell and/or bone marrow transplantation. Twenty-one children are waiting for their newborn siblings to gain sufficient weight and maturity for the donation of stem cells. The successful transplantations have been performed for the following indications: β- Thalassemia (n = 19), Wiskott Aldrich syndrome (n = 2), Glanzmann Disease (n = 1), X-Adrenoleukodystrophy (n=1) and acute myeloid leukemia (n = 1) and Diamond Blackfan anemia (n = 1). This data presents one of the world’s largest experiences on preimplantation HLA typing, and the outcome of stem cell transplantation is the largest number available from one center. Our results indicate HLA typing with or without mutation analysis is a promising and effective therapeutic tool for curation of an affected sibling. Full article

Thalassemia and abnormal haemoglobins are a serious health problem in Turkey. Very important steps for toward preventing thalassemia have been taken in Turkey by Ministry of Health (MOH), Turkish National Haemoglobinopathy Council (TNHC) and Thalassemia Federation of Turkey (TFT) since 2000. In 1993, a law was issued called Fight Against Hereditary Blood Disease especially for thalassemia and haemoglobinopathies. The law commends to prevent haemoglobinopathies and to treat all patients with haemoglobinopathy and thalassemia. A pilot project was started and centres were created in the MOH Hospitals in the southern provinces of Turkey. In 2000, TNHC was installed to combine all centres, foundations, and associations into one organization controlled by the MOH. In 2001, the MOH and the TNHC made an inventory of all recorded patients with thalassemia and abnormal hemoglobins in Turkey, registering at least 4513 patients. In 2002, written regulations for the Fight Against Hereditary Blood Disease were published. MOH and TNHC selected 33 provinces situated in the Thrace, Marmara, Aegean, Mediterranean and South Eastern regions with high birth prevalence of severe haemoglobinopathies. In 2003, the haemoglobinopathy scientific committee was set-up, a guidebook was published and a national Hemoglobinopaty Prevention Program (HPP) was started in these high risk provinces . This program is running in these provinces successfully. In 2005, TFT was established as a secular society organization instead of TNHC. In 2007, National Thalassemia Prevention Campaign (NTPC) was organized for public education by TFT. This campaign contributed very important supporting to HPP in Turkey, because totally 62.682 people such as health workers, students, teachers, demarches, religion officers and the other many people were educated for preventing thalassemia and haemoglobinopathies. In 2009, National Thalassemia Education Seminars (NTES) for health personnel have been planned in 26 cities by MOH and TFT. A total 3.600 health persons were educated on thalassemia prevention and therapy with NTES in 18 centres in 2009 and 2010. In conclusion, according to reports of MOH, 46 first level haemoglobinopathy diagnosis centres, 5 second level diagnosis and therapy centre and 5 third level prenatal diagnosis centre were setup and licenced in 30 cities between 2003 and 2009. While premarital screening tests were 30% of all couples in 2003, it increased continuously during 6 years and it reached 81% in 2008. The number of new born with thalassemias and hemoglobinopathies was 272 in 2002, it was decreased to 23 in 2008, as a result there has been an 90% reduction in new affected births.
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The following recommendations should be taken into account during the evaluation and elucidation of the complex hemoglobinopathies: (a) in complex hemoglobinopathies performing DNA studies on all family members might be essential; (b) complex gene-gene interactions offer major diagnostic challenges both at the technical and clinical level; (c) hematological & DNA analyses must be run in parallel. Some cases may be straight forward but others may require indepth DNA work-up; (d) co-inheritance of α-thalassemia offers added challenge as it may affect phenotype significantly; (e) sickle cell anemia (SS), co-inherited with a-thal, can be a phenocopy of Sβ⁰-thal. The HbA₂ increase can be mistaken for Sβ-thal. DNA Sequencing is imperative; (f) only a selected number of normal MCV, MCH, borderline HbA₂ cases must be referred for DNA analysis. However, in certain cases, following hematological and family evaluation, the β and δ genes may need to be sequenced; (g) DNA Sequencing will increasingly become the method of choice for screening and DNA mutation analysis. However, new methods like MLPA-which analyzes gene dosage- must be used more commonly to rule out deletion mutants to avoid false negative sequencing results; (h) these recommendations should be reviewed every 2–3 years reflecting new methods, new findings and new findings from ethnic groups.
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Anaemia causes lower oxygen transport to tissues, interfering with normal physical development and may interfere with exercise and sports in thalassemia and Sickle-Cell-Disease (SCD) l. Moreover, in SCD, the abnormal haemoglobin alters the erythrocyte shape and leads to pulmonary parenchymal damage, impaired vascular function and micro vascular complications. However, we now accept that, with regular blood transfusions and efficient oral or parenteral chelation modalities, many patients lead a normal development and life with little or no change from the lifestyle of their unaffected friends, although there are cognitive and emotional factors leading behaviour for participation in the social life and exercise, as studied by many scientists in Italy, United Kingdom, Greece and India.
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Large scale prevention programs for Thalassemia major or Sickle cell disease have already been set up in several places with high frequency of the deleterious genes. The Greek health authorities realized the magnitude of the problem and allowed the creation of a National Thalassemia Center in 1972. The incidence of thalassemia in Greece varies from 1–2 per cent up to 15%, the mean being around 8 per cent. With an annual number of births around 100,000, if no prevention measures are taken, the expected yearly number of newborns with thalassemia major in Greece should be of the order of 100–120. To these one should add a few decades of sickle cell patients, homozygotes or compound HbS/β-thalassemia heterozygotes. The total number of patients with thalassemia major now surviving is estimated at 4000 plus another 600–800 patients with sickle cell disease. The National Thalassemia Center Center defined a network of peripheral Thalassemia Units in the major regional hospitals of the country, let them provide free carrier identification to couples requesting the test. When both partners were identified as carriers, they were given preliminary information locally and were referred to the Central Laboratory in Athens for further genetic counselling and, if so decided, prenatal diagnosis. Prenatal diagnosis was provided initially by fetoscopy and fetal blood biosynthesis; this approach was soon replaced by chorionic villi sampling and molecular techniques. The number of prenatal diagnoses carried out yearly over the last decade appears to cover the needs; the number of positive diagnoses is very close to the expected 25%, which also excludes overdiagnosis. The overall evaluation of the the program is reflected in the number of infants who were admitted to the pediatric clinics of the country in need of transfusion over the years the program was functioning. In fact, over the past years this number has steadily decreased to approximately 10 missed diagnoses annually, but has not reached zero as expected, after all this effort. The function of a comprehensive program for the prevention of thalassemia and HbS disease in Greece over the last 25 years has helped enormously in (a) avoiding birth of several hundreds of children with thalassemia major, thus (b) securing the use of the available resources for the optimal care of the patients who are living to-day, and (c) allowing thousands of couples at risk to give birth to healthy children.
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Some studies demonstrate that a large proportion of copy drugs contain lower levels of active substances and higher impurity levels than reference drugs. The number of copy drugs failing to meet internationally recognised quality criteria consequences of patients receiving lower doses of active substances than expected. In addition, possible clinical effect of impurities must be considered. Counterfeiting of drugs exhibits a significant and growing threat to human health and public safety.
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Transfusion dependant patients are at risk of acquiring transfusiontransmitted viral infections including Hepatitis B virus (HBV) and Hepatitis C (HCV). These infections can lead to cirrhosis and hepatic cancer. Standard treatment, although with improved therapeutic results still exhibits resistance and relapses. New antiviral agents have been developed to further improve results and reduce adverse events. For hepatitis B, along with pegylated interferon α-2α, other drugs that have been approved include lamivudine, adefovir, entecavir, telbivudine and tenofovir, while emtricitabine and clevudine are awaiting FDA approval. Possible combination drug therapy may improve efficacy without engendering resistance. For hepatitis C, standard therapy has been the combination of Peg-IFN/Ribavarin. Genotype 1 of the virus, which is widespread in the USA and Europe, can be resistant to treatment especially with high viral load. Directly acting antiviral agents (DAAs), are being developed. These are: (i) HCV NS3 protease inhibitors, such as telaprevir and boceprevir, which are currently approved by the FDA. Several other compounds are in phase I-II development; (ii) NS5B polymerase inhibitors, which target HCV replication. These include mericitabine (a nucleoside analogue inhibitor) currently in phase III trials, and nonnucleiside inhibitors; (iii) New intreferons such as pgylated interferonl λ, which are also on trial. Triple therapy using pegylated IFNa/ Ribavarin along with telaprevir or boceprevir are also under trial.
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Sickle cell pain is a complex but frequently experienced symptom. Acute painful events in children can be managed effectively in the community with appropriate support and education. If hospital management is required, rapid access to a consistent, reliable and safe analgesic pathway is recommended to ensure a good standard of care. Use of oral opiates in addition to short acting easily administrable forms of analgesia and strict adherence to protocoled monitoring will enable the acute event to be well managed and the negative pain experience minimised. An important part of the outpatient evaluation is determining the impact pain events are having on the child’s quality of life. Addressing psycho-social aspects, defining and modifying precipitating factors, if any are identified, and having a holistic approach to pain management is helpful. Education and use of self-management techniques can also be productive. Use of sickle modifying interventions such as hydroxycarbamide therapy or transfusion therapy can have a significant impact on reducing the severity and frequency of the acute pain event.
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Sickle Cell Disease(SCD) is one of the most common hemoglobinopathies in the world which causes stroke. The management of stroke depends on the manifestations and the age of the patient. Especially in childhood, anatomic and physiological abnormalities of CNS may be a predisposing factors. Stroke mostly affects the distal segments of the Internal Carotid Artery, but also middle and anterior segments of the cerebral arteries are involved. The most important predisposing factors are the arterial malformations, stenosis and obstructions in cranial arteries, generally involving Internal Carotid Artery, frequently Proximal Middle Cerebral or Anterior Cerebral Arteries. After infarcts at brain vessels, most frequent clinical findings are hemiparesis or hemiplegia, impaired speech, focal seizures, gait disturbances. Risk factors for predisposing stroke are prior transient ischemia, baseline Hb decrease, acute chest sydrome within previous two weeks, systolic blood pressure rises, leucocyte increases. The patient with silent stroke or transient ischemic attacks may be asymptomatic or without neurological symptoms. Neuroimaging abnormalities may be seen without significant clinical findings in children with SCD. We talk about silent stroke if there are neuroradiological abnormalities without clinical findings. Children with silent strokes are more prone to new strokes. If there is a significant stroke a ischemic stroke often present with focal neurological signs and symptoms. If patient is asymptomatic or have suspected stroke, first step may be performance of Transcranial Doppler Ultrasonography (TCD). Children with time-averaged mean velocity (TAMV), measured in Middle Carotid Artery or in distal internal carotid Artery abnormally elevated, defined as TAMV ≥ 200 cm/sec, have sixfold increase for stroke than those with normal TAMV ≤ 170 cm/sec. For these patients under the risk of stroke, chronic blood transfusion is recommended for prevention of primary stroke events. Because of high oxygene demand in children, the child with SCD who also has anemia is at particular risk. The management of acute stroke includes to rule out hemorrhage, stabilize vital signs, careful use of hydration and RBCs transfusion. Exchange blood with normal RBCs is mandatory; it will improve tissue perfusion and oxygenation. Long-term management of stroke is directed to prevent recurrences with fluids supplementation, a chronic transfusion programme at least for 6 months with exchange transfusion or erythrocytapheresis for reducing the HbS under 30%. After 3 years of HbS levels to be maintained <30%, the HbS leveles can be raised safely to less than 50% if the patient has remained neurologically stable. Indefinite chronic transfusion programme was advised for the patients with abnormal TCD values. Hydroxyurea (HU) is an alternative therapy in reducing TCD values and to try to increase HbF improving the clinical outcome. Periodical cranial Doppler ultrasound examination and selective red blood cell transfusions ‘d be useful for stroke prevention.
镰状细胞病(SCD)是世上最常见的血红蛋白病，可致中风 中风防治受症状表现和病人的年龄所左右。 尤其对于患儿，中枢神经系统的组织异常和生理异常可能是诱病因素。 中风通常影响颈内动脉的末端，但也会牵连到脑动脉的中段和前段。 中风最重要的诱病因素有动脉畸形、器官狭窄和大脑动脉阻塞，一般和到颈内动脉有关，但牵连到大脑中动脉或大脑前动脉更为常见。 脑血管梗塞后，通常临床发现轻偏瘫或偏瘫、语言障碍、病灶性颠痫和步态障碍等。 诱病性中风具有的风险包括：前两周内引起短暂性局部缺血、血红蛋白含量减少和急性胸痛综合症，然后导致收缩压升高和白血球增加。 轻度中风或短暂性脑缺血发作的患者可能无症候或无神經症狀。 在没重大临床发现的情况下，镰状细胞病患儿可做脑神经成像检查，异常亦会发现。 下边我们将讨论无临床表现情况下神经放射性异常。 轻度中风的患儿再次中风的可能性很大。 如果中风严重，脑缺血的出现经常伴随着局部性神經系統症候和症状 如果患者无症候或疑似中风，首先应进行经颅多普勒超声（TCD）检查。 在异常抬升的中动脉或内动脉末端测量时间平均血流速度(TAMV)，结果为TAMV ≥ 200 cm/sec，该患者中风的可能性是正常情况（TAMV ≤ 170 cm/sec）的六倍。建议对有中风危险的患者采取慢速输血的方法，以防止主要中风事件。 由于儿童对氧的需求量高，患镰状细胞病同时伴有贫血的儿童危险系数尤其高。 急性中风防治的措施包括：排除溢血的可能性、稳定生命体征、谨慎利用水和作用和（血红细胞）RBCs输血 必须使用正常的RBCs交换血液；提高组织灌注和氧化作用。 中风的长期防治旨在阻止再次补充液体，用交换输血或红细胞除去法慢速输血至少6个月，以便把血红蛋白含量减少到30%以下。 血红蛋白含量 < 30% 保持3年后，如果患者神经稳定，可将其升高到50%以下。 TCD值不正常的患者，建议采取不定期慢速输血程序。 作为降低TCU值的备用疗法，羟基脲（HU）尝试提高HbF的含量，达到改善临床结果的目的。 防止中风有效的措施包括定期对大脑进行多普勒超声检查和有选择性的进行血红细胞输血。 Full article

Pain in thalassemia proves to be an emergent issue even if it is not possible to correlate it definitely to bone disease, but we strongly believe that a multidisciplinary approach, may be as decisive in this case as it was in the struggle against thalassemia. In fact, we strongly believe that the involvement of various specialists such as endocrinologists, orthopedist, anesthesiologist, in a close team coordinated by a specialist in thalassemia is absolutely necessary for achieving our aims. First of all, we need to implement clinical trials to identify the mechanisms of disease, to find the optimal management of the problem in order to provide new therapeutic methods for preventing the thalassemia-induced osteoporosis and to reduce the presence of very disabling pain for patients. Patients’ expectations for the future are to continuously improve the quality of life. To do that it is needed to identify pathways to prevent all the complications of thalassemia that cause widespread pain, above all osteoporosis. Although we have seen that osteoporosis is not the sole cause of pain for thalassemia patients, it is true that this seems to have a great incidence in thalassemia patients and it gives a significant contribute to an increased pain.
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Many thalassemia subjects both transfused Major (TM) and nontransfused Intermedia (TI) suffer from longstanding bone disease, reduced or low bone mass (osteopenia or osteoporosis), fractures and bone pain. Unexpected musculoskeletal disease occurs despite longstanding hypertransfusion and new iron chelation strategies. Conditions which have been implicated in its pathogenesis include the massive ineffective erythropoiesis, chronic hypoxia associated with anemia, the local metabolic dysfunction from hemochromatosis, iron chelation toxicity, trace mineral deficiencies such as zinc deficiency, low vitamin D concentrations, the effect of endocrine dysfunction such as hypoparathyroidism, hypogonadism and growth hormone deficiency from hemochromatosis and the chronic inflammatory state induced by iron excess. The pathogenesis of bone disease has been attributed to the underlying marrow expansion of medullary bone caused by the massive ineffective erythropoiesis and subsequent cortical thinning. The process of normal bone health is maintained by a metabolic interplay of several hormonal factors including growth hormone, estrogen, testosterone, parathyroid hormone all of which can be diminished by iron overload in Thalassemia. Trace metals and vitamins including calcium, copper, zinc or vitamin C can also be deficient from iron excess or iron chelation which are also important contributors to bone metabolism. Indeed toxicities of iron chelation itself on bone development in the growing child associated with zinc deficiency, high Deferoxamine dosing and low iron burdens or the collagenous joint disease associated with deferiprone chelation have further contributed to the current musculoskeletal disease of Thalassemias. Decreased spinal height, vertebral flattening and scoliosis have also been reported. Magnetic Resonance Imaging (MRI) of adolescent and adult β Thalassemia Major and Intermedia patients with osteoporosis and pain have assisted in defining the associated musculoskeletal pathology. The outcomes of the TCRN cross sectional observational study of low bone mass revealed the nature of bone disease across all ages and thalassemia syndromes and identified the prevalence and history of fractures and observed pain. Longstanding osteopenia and osteoporosis existed in the majority of subjects across all thalassemia syndromes. The TCRN Bone Study showed high prevalence of low BMD, fractures and bone pain in Thalassemia. A strong association between low bone mass and fractures was identified factors that may contribute to the pathogenesis of bone disease in Thalassemia. Bone mass was reduced even in children; 55% of 6–10 year olds had osteopenia or osteoporosis. Low vitamin D levels were also associated with increased pain in Thalassemia Major (p = 0.010). Pain has been associated with vitamin D deficiency and vitamin D abnormalities are prevalent in Thalassemia compared to the general population. Musculoskeletal disease of thalassemia may be related to the underlying disease, the consequences of iron excess, associated inflammatory mechanisms or iron chelator effects. Further studies are needed to identify its etiology and improve treatment strategies and prevent the emerging progressive osteoporotic disease process in thalassemia associated with high risk of fractures and musculoskeletal pain disrupting quality of life causing anxiety and depression into adolescence and adulthood.
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Iron overload due to multiple transfusions affects the endocrine glands especially the anterior pituitary, the pancreas, the thyroid and the parathyroids. This leads to a variety of endocrinopathies and growth failure. Delayed puberty, hypogonadism, growth hormone deficiency in adults, hypothyroidism, hypoparathyroidism and diabetes are common and around 20% of patients have more than one endocrinopathy. In this paper suggestions for guidelines concerning diagnosis, investigation and treatment are proposed for the following clinical entities encountered in thalassaemia patients: (i) Growth failure: after the age of 9–10 rears there is a slowing of growth velocity, the pathogenesis of which is multifactorial and anaemia, folate deficiency and hypersplenism are implicated. Desferrioxamine toxicity has been reported as cause of the abnormal upper to lower segment ratio. Growth hormone is given in selected cases. (ii) Delayed puberty and hypogonadism: are the most obvious clinical consequences of iron overload in both sexes. Primary and secondary amenorrhoea are very common in women. Sex steroid replacement therapy is the optimal therapeutic regime which has a great impact on the quality of life of adult thalassaemia patients. (iii) Fertility: Women with TM, who are regularly transfused and are well chelated can now become pregnant either spontaneously or by inducing ovulation. Pregnancy must carefully monitored. (iv) Growth hormone deficiency in adult thalassaemics: This occurs in a high prevalence and since GH in adults is involved in numerous biological functions, especially of the heart, proper assessment of this hormone is needed and consideration of the need for replacement. (v) Hypothyroidism and hypoparathyroidism: these deficiencies are also discussed.
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I would like to tell you a main message: to fight against this disease is always useful. Imagine you are a little kid and want to play with your friends, you want to run with them play ball with them but you couldn’t. You have to stay at home or sit on the side and watch it is a hard thing to do for a kid. However, the help of your parents, the encouragement and the patience of your doctors, the support of associations are crucial issues to continue the fight. Patients have to remember that continuing their treatments strictly is the main aim to reach in the next future the cure.
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Clinical advances in the treatment of thalassaemia major (TM) patients have helped to increase substantially the life expectancy of patients. The TM patients today represent the first generation of adult thalassemics. As patients enter puberty, they begin to experience a variety of endocrine abnormalities, presumably the results of chronic anaemia and tissue iron deposition from the chronic transfusion therapy. In patients with TM, the anterior pituitary gland is particularly sensitive to free radical stresses. Recent reports have documented a frequency of severe growth hormone deficiency in 13–32% of adult patients with TM. The prevalence of impaired adrenal function in TM patients has been reported from 0 to 33%, depends on the age of the population studied, although clinical adrenal insufficiency (AI) is rare. Thyroid dysfunction has been observed in 13–60% of patients, but its severity is variable in different series. Acquired central hypothyroidism (CH) is a rare complication. Full article

For the thalassaemia syndromes the Thalassaemia International Federation, the international patients’ organization has been struggling since its inception in 1987 to facilitate access to treatment for all thalassaemia patients across the globe. Ever since we accepted the doctrine that where strong patient organisation exists, we have observed that there has been a marked improvement in the health care services provided for the haemoglobin disorders worldwide. Unfortunately personality or ego issues and lack or inexperience of strategic planning have always proved to be major drawbacks in achieving collective goals for patients. But the biggest obstacle to access to treatment in the years of my early adulthood has been no other than my self. Having finally secured safe and adequate blood, sample chelating agents and excellent medical professionals, I had decided that I had enough and I stopped chelating. I know now that the access to treatment has as much to do with our determination to live and prosper as with the influence of our countrymen to provide to the less privileged. My disorder provided me with much more than I could ever pray for… Thank God.
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Among the factors associated with thalassemic heart disease, endocrine disturbance is also a contributing factor. We present a retrospective, cross sectional study, which aims to establish the prevalence of cardiac complications in thalassaemia major (TM) patients with endocrine complications and to evaluate the influence of endocrine disease on cardiac complications. Endocrinological and cardiological parameters were considered on 957 TM patients who are enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network in 68 sites in Italy. Patients with pubertal hypogonadism (163 males and 175 females), hypothyroidism (192), diabetes mellitus (87) and hypoparathyroidism (61), were compared according to cardiac complications: global heart T2*, cardiac dysfunction, heart failure, arrythmias, pulmonary hypertension and myocardial fibrosis. Control groups were made up according to the age range of patients with the corresponding endocrinopathy. The prevalence of cardiac dysfunction, arrhythmias and heart failure was significantly increased in patients with endocrinopathies. Cardiac complications tended to increase according to the number of endocrinologies affecting the patient. Aim of our retrospective and cross sectional study was to establish the prevalence of cardiac complications in thalassemia major (TM) patients with endocrine diseases and to evaluate the influence of endocrine diseases on cardiac complications.
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Pulmonary hypertension (PH) is one of the main cardiovascular complications in haemoglobinopathies and is considerably implicated in patients’ morbidity and mortality. In thalassemia intermedia, PH is found in about 60% of traditionally managed patients and represents the main cause of heart failure. In sickle cell anemia, PH is encountered in one third of patients and has been found to be a strong and independent predictor of mortality, while in sickle thalassemia, PH is generally less frequent and severe. The pathophysiology of PH in haemoglobinopathies is multifactorial and several mechanisms seem to be implicated, including a complex vasculopathy, hypercoagulability and elastic tissue defects, all associated with chronic hemolysis, high output state due to chronic anemia, as well as left heart dysfunction, pulmonary disorders and thromboembolic complications. Echocardiography is the most useful tool for patients’ screening on a regular basis, while the diagnosis of PH should always be confirmed by right cardiac catheterization. The proper management of the disease itself with haematological modalities such as blood transfusions combined with iron chelation or hydroxyurea, is the most effective approach for the prevention and treatment of haemoglobinopathy-associated PH. Antithrombotic agents should also be considered while the value of novel agents used in the treatment of pulmonary arterial hypertension, including endothelin antagonists or phosphodiesterase-5 inhibitors, is not yet established in patients with haemoglobinopathies.
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The use of Magnetic resonance imaging (MRI) to estimate tissue iron was initiated nearly three decades ago but has only become a practical reality in the last ten years. MRI is most often used to estimate hepatic and cardiac iron in patients with thalassemia or sickle cell disease and has largely replaced liver biopsy for liver iron quantification. The ability of MRI to image extra hepatic organs has really transformed our understanding of iron mediated toxicity in transfusional siderosis. For decades, iron cardiomyopathy was the leading cause of death in thalassemia major, but it is now relatively rare in centers with regular MRI screening. Early recognition of cardiac iron loading allows more gentle modifications of iron chelation therapy prior to life threatening organ dysfunction. Serial MRI evaluations have demonstrated differential kinetics of uptake and clearance among the difference organs of the body. Although elevated serum ferritin and liver iron concentration increase the risk of cardiac and endocrine toxicities, extra hepatic iron deposition and toxicity occurs in many patients despite having low total body iron stores; there is no safe liver iron level in chronically transfused patients. Instead, the type, dose, and pattern of iron chelation therapy all contribute to whether cardiac iron accumulation will occur. These observations, coupled with the advent of increasing options for iron chelation therapy, are allowing clinicians to more appropriately tailor chelation therapy to individual patient needs, producing greater efficacy with fewer toxicities. With the decline in cardiac mortality, future frontiers in MRI monitoring including better prevention of endocrine toxicities, particularly hypogonadotropic hypogonadism and diabetes. These organs also serve as early warning signals for inadequate control of non-transferrin bound iron, a risk factor for cardiac iron loading. Thus MRI assessment of extra hepatic iron stores is a critical monitoring tool for chronically transfused patients. Further prospective work is necessary to determine whether markers of endocrine and exocrine pancreatic function can be used as surrogates of cardiac risk in regions where MRI is not available.
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Heart failure always represented and still remains the leading cause of mortality in β (β)-thalassemia, despite the therapeutic advances and the considerable amelioration of prognosis accomplished over the last decades. High cardiac output due to chronic anemia and myocardial iron overload due to repetitive blood transfusions are the two main pathogenetic mechanisms causing heart failure in β-thalassemia. In regularly treated thalassemia major patients, left ventricular dysfunction, resulting mainly from myocardial siderosis, is considered to be the primary cause of heart failure and thus the prevention, early recognition and effective management of iron overload is of key importance. However, the spectrum of cardiovascular complications that may ultimately lead to heart is wide and should be individually investigated in each one of the patients. Echocardiography is the main modality used for the regular follow-up and screening of asymptomatic patients and for the evaluation of patients with cardiac symptoms, while the T2* relaxation time provided by magnetic resonance imaging allows the accurate identification and quantification of myocardial iron burden and thus the proper guidance of iron chelation therapy.
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As the life expectancy of β-thalassemia patients has markedly improved over the last few decades, several manifestations are increasingly recognized. The presence of a high incidence of thromboembolic events, mainly in thalassemia intermedia patients, has led to the identification of a hypercoagulable state in thalassemia. In this review, the current clinical experience attributed to the coagulopathy in thalassemia intermedia patients is summarized. Recommendations for thrombosis prophylaxis are also discussed. Full article

Thalassemia intermedia (TI) is a heterogeneous disease, in terms of both clinical manifestations and underlying molecular defects. Some TI patients are asymptomatic until adult life, whereas others are symptomatic from early childhood. In contrast with patients with Thalassemia major (TM), the severity of anemia is less and the patients do not require transfusions during at least the first few years of life. Many patients with TI, especially older ones, have been exposed to the multiple long-term effects of chronic anemia and tissue hypoxia and their compensatory reactions, including enhanced erythropoiesis and increased iron absorption. Bone marrow expansion and extramedullary hematopoiesis lead to bone deformities and liver and spleen enlargement. Therapeutic strategies in TI are not clear and different criteria are used to decide the initiation of transfusion and chelation therapy, modulation of fetal hemoglobin production, and hematopoietic stem cell transplantation on an individual basis. The clinical picture of well-treated TM patients with regular transfusionchelation therapy is better from TI patients who have not received adequate transfusion therapy. There is a significant role of early blood transfusion to prevent and treat complications commonly associated with TI, such as extramedullary erythropoiesis and bone deformities, autoimmune hemolytic anemia, leg ulcers, gallstones, pseudoxantoma elasticum, hyperuricosuria, gout and pulmonary hypertension, which are rarely seen in thalassemia major. Nowadays, indications of transfusion in patients with TI are chronic anemia (Hb < 7 g/dL), bone deformities, growth failure, extramedullary erythropoiesis, heart failure, pregnancy and preparation for surgical procedures. Conclusion: Adequate (regular or tailored) transfusion therapy is an important treatment modality for increasing the quality of life in patients with thalassemia intermedia during childhood. Full article

α-thalassaemia is an autosomal recessive disorder, in which there is impaired production of the a-globin chains of haemoglobin. It is associated with microcytic hypochromic anaemia, and a clinical phenotype varying from almost asymptomatic to a lethal haemolytic anaemia. It is probably the most common single gene disorder worldwide, and is especially frequent in populations originating from the Mediterranean region, SE Asia, Africa, Middle East and Indian subcontinent.
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This study aims to describe the creation process of standard procedures to make possible multicentre studies related to emotional aspects of thalassaemic patients, their families and caregivers; and the pilot phase of the routine implementation. The objectives defined to perform this goal are: (i) develop routines to assess and manage/treat emotional issues; (ii) adjust the ABRASTA - Brazilian Association of Thalassaemia computer system to the input of collected data and its compilation; (iii) conduct a pilot implementation of the routines; (iv) discuss the whole process and propose next steps. Forty patients were assisted following the above mentioned routines of psychological evaluation, follow-up assistance and management of specific emotional issues. Conclusions are that the routines are adequate to enable multicenter research to compare findings and develop specific interventions to Thalassaemia patients, their families and caregivers; information gathered through them is an important means of supporting medical doctors and other members of the professional team, both in the therapeutic planning and in the communication process with patients and families; finally, considering the nature of the information, psychologists and psychiatrists are the most indicated professionals to perform the assessment and the interventions related to emotional issues, due to their professional background, training and specific skills that allow a free and candid communication with the patients and their families.
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